HMGB1 binds to the <i>KRAS</i> promoter G-quadruplex: a new player in oncogene transcriptional regulation?

Amato, Jussara; Madanayake, Thushara W.; Iaccarino, Nunzia; Novellino, Ettore; Randazzo, Antonio; Hurley, Laurence H.; Pagano, Bruno

doi:10.1039/c8cc03614d

Cited by 56 publications

(42 citation statements)

References 31 publications

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“…The NHE in the KRAS proximal promoter is highly abundant in G-rich sequences, and several transcription factors interact with a G4 structure formed in this region (Figure 8a) [176,177,178]. A polypurine G-rich element, located approximately –300 to –100 nucleotides upstream of the exon 0/intron 1 boundary in a murine or human genome, is likely to be a component of the promoter activity, and includes multiple PQSs [45,46,176,177,178,179,180]. Importantly, pyrene-modified oligonucleotides that were devised to be a more stable form of the KRAS G4 formed in the PQS1 were able to attract the factors essential for transcription and to exhibit a strong antiproliferative activity through a G4-decoy effect in pancreatic cancer cells [181].…”

Section: Cancer-related G-quadruplexes and Their Interacting Molecmentioning

confidence: 99%

Recent Progress of Targeted G-Quadruplex-Preferred Ligands Toward Cancer Therapy

et al. 2019

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A G-quadruplex (G4) is a well-known nucleic acid secondary structure comprising guanine-rich sequences, and has profound implications for various pharmacological and biological events, including cancers. Therefore, ligands interacting with G4s have attracted great attention as potential anticancer therapies or in molecular probe applications. To date, a large variety of DNA/RNA G4 ligands have been developed by a number of laboratories. As protein-targeting drugs face similar situations, G-quadruplex-interacting drugs displayed low selectivity to the targeted G-quadruplex structure. This low selectivity could cause unexpected effects that are usually reasons to halt the drug development process. In this review, we address the recent research on synthetic G4 DNA-interacting ligands that allow targeting of selected G4s as an approach toward the discovery of highly effective anticancer drugs.

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Section: Cancer-related G-quadruplexes and Their Interacting Molecmentioning

confidence: 99%

Recent Progress of Targeted G-Quadruplex-Preferred Ligands Toward Cancer Therapy

et al. 2019

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“…HMGB1 has been identified as a binding partner of telomeric G4 in a pull‐down assay and the initial in vitro comparative studies with promoter G4s confirmed HMGB1 selectivity for the telomeric quadruplex structure . However, subsequent studies revealed that HMGB1 also has a high affinity for the KRAS promoter G4 . While most noncanonical DNA structures are unwound by HMGB1, G4s are not (for the KRAS G4, substantial HMGB1‐induced stabilization was reported).…”

Section: G4s Might Directly Engage Architectural Chromatin Proteins mentioning

confidence: 99%

“…However, subsequent studies revealed that HMGB1 also has a high affinity for the KRAS promoter G4 . While most noncanonical DNA structures are unwound by HMGB1, G4s are not (for the KRAS G4, substantial HMGB1‐induced stabilization was reported).…”

Section: G4s Might Directly Engage Architectural Chromatin Proteins mentioning

confidence: 99%

DNA G‐Quadruplexes (G4s) Modulate Epigenetic (Re)Programming and Chromatin Remodeling

2019

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Here, the emerging data on DNA G‐quadruplexes (G4s) as epigenetic modulators are reviewed and integrated. This concept has appeared and evolved substantially in recent years. First, persistent G4s (e.g., those stabilized by exogenous ligands) were linked to the loss of the histone code. More recently, transient G4s (i.e., those formed upon replication or transcription and unfolded rapidly by helicases) were implicated in CpG island methylation maintenance and de novo CpG methylation control. The most recent data indicate that there are direct interactions between G4s and chromatin remodeling factors. Finally, multiple findings support the indirect participation of G4s in chromatin reshaping via interactions with remodeling‐related transcription factors (TFs) or damage responders. Here, the links between the above processes are analyzed; also, how further elucidation of these processes may stimulate the progress of epigenetic therapy is discussed, and the remaining open questions are highlighted.

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“…Figure 2 shows SPR sensorgrams obtained by injecting increasing concentrations of GROs over the nucleolin-functionalized sensor-chip surface by using the single-cycle kinetics (SCK) method. SCK was preferred to the multi-cycle kinetics because, using this method, the regeneration step (which is detrimental to the protein) is performed only at the end of the complete binding cycle, thus allowing the chip surface and immobilized protein to last longer [ 35 , 36 ]. The GROs (analytes) were injected from a low to high concentration with short dissociation times in between and a long dissociation time at the end.…”

Section: Resultsmentioning

confidence: 99%

Toward G-Quadruplex-Based Anticancer Agents: Biophysical and Biological Studies of Novel AS1411 Derivatives

Ogloblina

Iaccarino

Capasso

et al. 2020

IJMS

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Certain G-quadruplex forming guanine-rich oligonucleotides (GROs), including AS1411, are endowed with cancer-selective antiproliferative activity. They are known to bind to nucleolin protein, resulting in the inhibition of nucleolin-mediated phenomena. However, multiple nucleolin-independent biological effects of GROs have also been reported, allowing them to be considered promising candidates for multi-targeted cancer therapy. Herein, with the aim of optimizing AS1411 structural features to find GROs with improved anticancer properties, we have studied a small library of AS1411 derivatives differing in the sequence length and base composition. The AS1411 derivatives were characterized by using circular dichroism and nuclear magnetic resonance spectroscopies and then investigated for their enzymatic resistance in serum and nuclear extract, as well as for their ability to bind nucleolin, inhibit topoisomerase I, and affect the viability of MCF-7 human breast adenocarcinoma cells. All derivatives showed higher thermal stability and inhibitory effect against topoisomerase I than AS1411. In addition, most of them showed an improved antiproliferative activity on MCF-7 cells compared to AS1411 despite a weaker binding to nucleolin. Our results support the hypothesis that the antiproliferative properties of GROs are due to multi-targeted effects.

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HMGB1 binds to the KRAS promoter G-quadruplex: a new player in oncogene transcriptional regulation?

Cited by 56 publications

References 31 publications

Recent Progress of Targeted G-Quadruplex-Preferred Ligands Toward Cancer Therapy

Recent Progress of Targeted G-Quadruplex-Preferred Ligands Toward Cancer Therapy

DNA G‐Quadruplexes (G4s) Modulate Epigenetic (Re)Programming and Chromatin Remodeling

Toward G-Quadruplex-Based Anticancer Agents: Biophysical and Biological Studies of Novel AS1411 Derivatives

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